Genetic testing for dilated cardiomyopathy in clinical practice

Abstract

Background: Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations.

Methods and results: We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, ACTC, LMNA, PLN, TAZ, and LDB3), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7, LMNA, or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing.

Conclusions: Using rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.

Fig. 1

Family genetic studies indicate that 3 MYBPC3 variants previously reported to be pathogenic do not cause dilated cardiomyopathy (DCM). Combined clinical and genetic evaluation (segregation studies) provided valuable information in assessing the likelihood that a DNA variant causes disease. The absence of the variant in affected family members (circled) provides strong evidence that the variant is not pathogenic. Information supportive of phenotype is provided below the circled nonsegregant individuals. Filled symbols indicate affected individuals, squares males, circles females, arrows the index patient for genetic testing. Genotypes (+ or −) indicate the presence or absence of the familial variant. Dx, age at diagnosis; HCM, hypertrophic cardiomyopathy; LV mod dil, moderate left ventricular dilation.

Fig. 2

Family history (FH) and age influence the sensitivity of genetic testing. In the absence of a family history of disease, no adult dilated cardiomyopathy patients >40 years old were found to have a mutation. Seventeen patients with unknown family history were excluded. *Mutation refers to the presence of a clinically significant variant.